In humans, excessive adiposity, or body weight, is a problem bordering on obsession in certain populations, particularly in Western cultures. Popular weight loss methods extend from behavioral regimes to pharmaceutical therapies, encompassing a vast spectrum of diets, diet aids, exercise programs and alleged miracle cures. However, among these methods, very few are specifically directed toward modulating the known biochemical processes of adipose synthesis and metabolism.
According to one prevailing hypothesis, most mammals (including humans) produce adipose tissue through adipose tissue lipoprotein lipase (ATLPL) hydrolysis of fatty acids from the triglycerides of circulating triglyceride-rich lipoprotein. The released fatty acids are taken up by adipocytes, converted to triglycerides, and stored. Thus, the so-called "lipoprotein lipase hypothesis" holds that ATLPL particulates in the preferential production of adipose tissue from excess fat calories (see, e.g., Isselbacher et al. "Harrison's Principles of Internal Medicine", Vol. 1, Part 5, p. 448 (McGraw-Hill, 1994)). Hypertriglyceremia and hyperlipoproteinemia conditions have been associated with obesity through excessive hepatic secretion of triglycerides in response to increased levels of free fatty acids in plasma (id. at p. 449).
To date, the common pharmaceutical approaches to weight management have been principally palliative, involving administration of anorexiants (generally amphetamine-like agents to suppress appetite) or thyroid hormone (where obesity is related to hyperthyroidism) (id. at p. 551). Neither approach is targeted to the biochemical pathways associated with adipose formation.
In contrast, research regarding the pharmaceutical control of excessive lipid levels in serum and body organs (particularly the liver and vessels of the cardiovascular system) has been extensive in recent years. For example, since about 1980, pharmaceutical hypolipidic agents began to be tested in animals and humans for their effect on circulating levels of lipids and cholesterol for treatment of diseases of the liver and cardiovascular system. One such hypolipidic agent studied is pantethine, a disulfide linked pantetheine dimer in which each dimeric unit includes pantothenic acid (vitamin B.sub.3) linked to .beta.-mercaptoethylene. Pantethine has a molecular weight of 554.7 g/mol and has the following structure: ##STR1## Pantethine is an intermediate in the metabolic pathway for biosynthesis of acetyl coenzyme A (CoA).
Pantethine has been used clinically and/or experimentally to deliver cysteamine to reduce plasma and pituitary prolactin in humans (Jeitner and Oliver, J. Endocrinol., 124: 397-402, 1990), to reduce total serum cholesterol and triglyceride levels in human patients suffering from, or at risk for, cardiac disease (Arsenic et al., Acta. Biomed. Ateneo Parmense, 58: 143-152, 1987; U.S. Pat. No. 4,571,401 to Picciola et al.), to limit hepatic lipid storage in chickens (Hsu et al, Poult. Sci., 66: 280-286, 1987), to limit hepatic fibrosis in humans (U.S. Pat. No. 4,937,266 to Tomikawa et al.), and to inhibit phase separation of ocular lens proteins for treatment of cataract conditions. Pantethine has also been shown to be atoxic in animals and humans (see, e.g., Donati et al., Clin. Nephrol., 25: 70-74, 1986; Arsenic et al., supra). A pantetheine derivative, pantetheine-S-sulfonic acid, has been employed to improve lipid metabolism (U.S. Pat. No. 4,568,683 to Suga et al.).
However, to date, pantethine per se has not been widely used to treat abnormal lipid accumulation and metabolism in humans (Harrison's Principals of Internal Medicine, supra at pages 450 and 1112-1113), and has not been suggested as a possible pharmaceutical agent of use in the control of excessive adipose deposition in animals or humans.
A continuing need exists for effective compositions and treatment regimens for the control of excessive adipose deposition in mammals.